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Melatonin Treatment for Tardive Dyskinesia
A Double-blind, Placebo-Controlled, Crossover Study
Eyal Shamir, MD;
Yoram Barak, MD;
Irena Shalman, MD;
Moshe Laudon, PhD;
Nava Zisapel, PhD;
Ricardo Tarrasch, MA;
Avner Elizur, MD;
Ronit Weizman, MD
Arch Gen Psychiatry. 2001;58:1049-1052.
ABSTRACT
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Background Antipsychotics remain the mainstay of drug intervention in the management
of schizophrenia. However, long-term treatment with antipsychotics is associated
with a variety of movement disorders, the most disabling of which is tardive
dyskinesia (TD), which occurs in up to 50% of patients hospitalized with chronic
schizophrenia. The pathophysiology of TD is still unclear and no definite
treatment exists. Both dopamine receptor supersensitivity and oxidative stress–induced
neurotoxicity in the nigrostriatal system are apparently implicated. The pineal
hormone melatonin is a potent antioxidant and attenuates dopaminergic activity
in the striatum and dopamine release from the hypothalamus. Thus, it may have
a beneficial effect for both the treatment and prevention of TD.
Methods Using a double-blind, placebo-controlled, crossover study, we evaluated
the efficacy of 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia
and TD. The primary outcome measure was the change from baseline in Abnormal
Involuntary Movement Scale (AIMS) score.
Results The decrease (mean ± SD) in AIMS score was 2.45 ± 1.92
for the melatonin and 0.77 ± 1.11 for the placebo treatment groups
(P<.001). No adverse events or side effects were
noted.
Conclusion This is the first clinical evidence for efficacy of melatonin in the
treatment of TD.
INTRODUCTION
SCHIZOPHRENIA IS a chronic, usually lifelong psychiatric disorder that
requires many hospitalizations and complex psychosociobiological interventions.
Blockade of the postsynaptic dopamine D2 receptor by antipsychotic
medications results in improvement of psychosis in schizophrenia. However,
a broad spectrum of hyperkinesias is associated with long-term exposure to
these drugs. Tardive dyskinesia (TD) is estimated to occur in 3% to 5% of
patients treated with antipsychotics during the first 5 years of treatment
and 68% after 20 to 25 years of exposure to typical antipsychotics.1, 2, 3, 4 The introduction
of atypical antipsychotics reportedly lowers the risk of TD.5
However, TD is often refractory to treatment despite the numerous approaches
attempted throughout the years.6 Thus, there
is a need for more rigorous studies to assess the role of new strategies,
such as vitamin E and branched chain amino acids, in the treatment of TD.6, 7
The pathophysiology of antipsychotic-induced TD is still considered
unclear and controversial.8 Antioxidants, specifically
vitamin E, have been studied as possible agents for both the treatment and
prevention of TD. Meta-analysis of published studies demonstrates a modest
effect in reducing severity and a better outcome in new-onset TD.6 However, a multicenter, long-term, well-controlled,
randomized Veterans Affairs trial of vitamin E vs placebo in a large cohort
found no evidence for efficacy of vitamin E in the treatment of TD.9 Melatonin is 6 to 10 times more effective as an antioxidant
than vitamin E and exerts its actions through detoxification of a variety
of free radicals and stimulation of several antioxidant enzymes.10
Moreover, recent evidence makes melatonin an even more tempting candidate
for study in the treatment of TD. Pineal calcification and low endogenous
melatonin levels have been associated with TD in patients with schizophrenia
who are treated with antipsychotics.11 Melatonin
has been shown to exert antioxidant effect on dopaminergic neurons12 as well as dopaminergic-modulating activities13 and thus may be efficacious in the treatment of TD.
The aim of the present study was to evaluate the effect of melatonin on TD
in a double-blind, placebo-controlled, crossover study.
SUBJECTS AND METHODS
SUBJECTS
Twenty-four patients with schizophrenia were recruited from the inpatient
psychiatry service of the Abarbanel Mental Health Center (Bat-Yam, Israel).
Diagnosis of schizophrenia was established following a structured interview
(Structured Clinical Interview for DSM-IV) administered
by a board-certified psychiatrist (E.S. or Y.B.). All patients met DSM-IV criteria for both schizophrenia and antipsychotic-induced TD.
Exclusion criteria were comorbid neurological illness, substance abuse, and
concurrent participation in another study.
Twenty-four patients were eligible and included in the randomization
phase. Randomization was performed using sealed envelopes. Two female patients
were discharged from the hospital before initiation of the study and are not
included in the analysis. The mean ± SD age of the 22 patients (11
women and 11 men) was 64.2 ± 14.3 years (range, 28-82 years). The mean
± SD duration of illness was 24.8 ± 8.7 years (range, 13-43
years; median, 23.5 years). Current antipsychotic medications were as follows:
haloperidol, 13 patients; chlorpromazine, 4 patients; perphenazine, 3 patients;
and zuclopenthixol, 2 patients. The antipsychotic medication regimens remained
unchanged throughout the study. Average dose of current antipsychotic medications
was 202.2 mg/d of chlorpromazine equivalents. Additional concomitant medications
were as follows: anticholinergics, 12 patients; benzodiazepines, 5 patients;
antidepressants, 4 patients; and mood stabilizers, 5 patients. The regimens
of these additional medications also remained unchanged throughout the study.
All study patients were previously and currently hospitalized in our center.
Mean cumulative lifetime exposure of the patients randomized to neuroleptic
medications was 3.82 x 106 mg of chlorpromazine equivalents
(SD, 3.7 x 106 mg; median, 2.4 x 106 mg;
range, 0.70-13.14 x 106 mg).
Information on the cumulative and current medications was recorded from
patients' medical charts.
PROCEDURE AND OUTCOME MEASURES
In a randomized, double-blind, crossover design, each patient was given
2 tablets (5 mg each, 10 mg/d) of controlled-release melatonin (Circadin;
Neurim Pharmaceuticals Ltd, Tel Aviv, Israel) or 2 placebo tablets identical
in appearance. Tablets were administered at 8 PM every night for 6 weeks.
After a washout period (following melatonin or placebo treatment) of 4 weeks,
the patients received 6 weeks of treatment with the other preparation. Both
patients and physicians were blinded to group allocation. Medication and placebo
were dispensed by the hospital's pharmacy and added to the patients' ongoing
treatment regimen. Treatment with a controlled-release dosage form was chosen
because it mimics the pattern of melatonin's endogenous profile.14
The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess TD severity,
since it has been shown to have good psychometric properties15
and is generally accepted as an outcome measure sensitive to changes in TD
in pharmacological trials.16 The AIMS was administered
by a single psychiatrist (I.S.) between 10 AM and noon, at baseline, and at
the end of weeks 6 (end of phase 1), 10 (end of washout period), and 16 (end
of phase 2). Severity of movements was rated on a scale of 0 to 4. The mean
± SD total AIMS score (items 1-7) in this population at baseline was
10.50 ± 5.30 (range, 3-22). The study protocol was approved by the
institutional review board (Abarbanel Mental Health Center) and the Israeli
Ministry of Health Committee for Studies in Human Subjects. Written informed
consent was obtained from all participants following a detailed explanation
of the nature of the study.
STATISTICAL ANALYSIS
The incomplete data from the 2 dropout patients were not included in
the analyses. Change in AIMS score (treatment period vs baseline or washout
period) with melatonin and placebo was calculated for each patient. To check
whether the effect of melatonin differed from that of placebo, the Wilcoxon
signed rank test was performed comparing the 2 effects; the  level
of significance was set at .05. To test whether there was a significant difference
in the effect of melatonin when given before or after placebo, the Mann-Whitney-Wilcoxon
test was performed on the ranks of the differences between the 2 measurements
(placebo, melatonin) of the AIMS score of each patient, comparing the placebo-melatonin
group vs the melatonin-placebo group. Data are presented as mean ±
SD.
RESULTS
After unblinding code following database lock, it was found that 10
patients (5 women and 5 men; mean age, 62.8 ± 11.4 years) received
placebo first and 12 patients (6 women and 6 men; mean age, 65.4 ±
16.6 years) received melatonin first. No adverse events or side effects possibly,
probably, or definitely related to the study medication were recorded during
the study.
Following 6 weeks of treatment with melatonin, the mean AIMS score (items
1-7) decreased from 10.27 ± 5.38 (range, 3-22) to 7.82 ± 4.82
(range, 1-20). Treatment of the same patients with placebo resulted in a decrease
in AIMS score from 9.09 ± 4.25 (range, 3-21) to 8.32 ± 4.18
(range, 3-21).
The decrease in AIMS score from baseline (or washout) values was significantly
higher with melatonin treatment compared with placebo (2.45 ± 1.92
vs 0.77 ± 1.11, respectively; Wilcoxon signed rank test, z = -3.27, 2-tailed P = .001). Of the
22 patients, 17 patients' symptoms improved more with melatonin than with
placebo, in 4 there was no difference between the 2 treatments, and only 1
patient's condition improved with placebo more than melatonin.
Individual patient data on the change from baseline (or washout) in
total AIMS score are shown in Figure 1.
There was no significant difference between the total AIMS score at the end
of the washout period and baseline, indicating that washout was long enough.
In addition, there was no significant difference between change in AIMS score
with different order of treatment, ie, placebo-melatonin vs melatonin-placebo
( 2 = 0.13; P = .72, Mann-Whitney-Wilcoxon
test).
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Improvement of total Abnormal Involuntary Movement Scale (AIMS) score
as a function of baseline AIMS score in patients taking either melatonin (10
mg, controlled release) or placebo. After 6 weeks of treatment, patients entered
a 4-week washout period and then crossed over for an additional 6 weeks of
treatment. The AIMS was scored at baseline and at the end of weeks 6 (end
of first treatment period), 10 (end of washout period), and 16 (end of second
treatment period, after crossover).
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Clinically significant outcome in the treatment of TD is usually defined
as a reduction in total AIMS score greater than 3 points.16
In the present study, 7 patients showed clinical improvement during the melatonin
treatment compared with only 1 during placebo treatment (McNemar test, 2 = 11.53, P<.001). In addition, only 2
patients showed no change in AIMS score during melatonin treatment, whereas
11 patients showed no change during the placebo treatment (McNemar test, 2 = 6.67, P<.01) (Figure 1). Improvement by 30% or more was noted in 9 of the 22 patients
treated with melatonin and in none given placebo.
COMMENT
These results indicate efficacy of melatonin treatment for 6 weeks in
treating TD in a placebo-controlled trial. The effects of melatonin (a mean
decrease of 2.45 ± 1.92 with melatonin compared with 0.77 ±
1.11 with placebo from baseline scores of 10.27 ± 5.38 and 9.09 ±
4.25, respectively) compare favorably with those attained by treatment with
vitamin E (1200 IU/d) for the same period (6 weeks). With vitamin E, mean
improvement in the AIMS score was reported to be 1.2 to 2.0 vs 0.2 to 2.0
with placebo,9, 17, 18, 19, 20, 21, 22
but the significance of vitamin E treatment vs placebo was not unequivocally
demonstrated. It remains to be studied whether the efficacy of melatonin will
further increase with longer treatment or with larger doses of the hormone.
The clinical efficacy of melatonin in TD may be explained by its antioxidant
properties. Oxidative stress and elevated levels of lipid peroxidation have
been implicated in haloperidol toxicity.23, 24
Evidence to support these animal studies includes elevated levels of lipid
peroxidation with haloperidol treatment in patients with psychoses.24 Furthermore, addition of the antioxidant vitamin
E to ongoing haloperidol treatment results in some improvement in patients
with TD symptoms.6 Melatonin was shown to be
a potent antioxidant in vitro and in vivo.10
Specifically, it has been shown to prevent haloperidol-induced oxidative neurotoxicity23 and 6-hydroxydopamine–induced neuronal death
in the nigrostriatal dopaminergic system.12
In addition, melatonin enhances the expression of glial cell line–derived
neurotrophic factor, a growth factor preferentially selective for dopamine
neurons.25 Such neuroprotective mechanisms
may be relevant to the anti-TD effect of melatonin.
Theoretically, a neuroprotective effect should prevail after the cessation
of drug use and is expected to be more pronounced in patients who have a lower
cumulative exposure to antipsychotics (because those presumably have a lesser
and perhaps reversible neurodegenerative damage). Yet, we found that the order
of administration of placebo and melatonin in our crossover designed trial
did not significantly alter the outcome of the treatment. Moreover, treatment
was more effective in patients who had worse symptoms (higher AIMS score)
at baseline. It seems, therefore, that the effect of melatonin is mostly pharmacological.
However, given the brevity of the present investigation, we cannot rule out
the possibility that some neuroprotection might also be involved.
It is proposed that TD is associated with dopamine receptor supersensitivity4; thus, the beneficial effects of melatonin in TD may
be due to modulatory effect on dopamine release. Inhibition by melatonin of
dopamine release from specific brain areas has been demonstrated in vitro
in rats,13 sheep, and hamsters.26
In addition, melatonin was able to reduce excitability of nigrostriatal neurons27 and increase the affinity of dopamine D2
receptors in the rat striatum.28 The relevance
of these mechanisms to TD in humans remains to be elucidated.
A reduction in nigrostriatal dopaminergic activity could theoretically
lead to worsening of parkinsonian adverse effects and akathisia, as is supported
by findings in animal models of Parkinson disease.29
Although we did not observe any such effects of melatonin in our study, this
possibility warrants further investigation. Notably, in a previous study,30 we found that a lower dose of melatonin (2 mg/d)
for a shorter period (4 weeks) was not significantly different from placebo
in the treatment of TD. Thus, it appears that the beneficial effect may be
dose and/or duration dependent.
The limitations of the present study are the relatively small sample
size, midrange duration of treatment, and the fact that the patients were
all inpatients, possibly reflecting more severe and chronic illness. An additional
limitation is the absence of systematic quantification of other movement disorders
during melatonin treatment, possibly hindering the ability to speculate on
the mode of action of melatonin treatment in TD.
In conclusion, the results of the present study demonstrate that melatonin
treatment is beneficial for antipsychotic-induced TD. To our knowledge, this
is the first study to demonstrate clinically meaningful improvement of TD
symptoms with melatonin. The brevity of our studies does not allow us to speculate
on whether melatonin is able to reverse the neural pathologic condition. This
issue needs to be investigated with larger samples and longer treatments.
AUTHOR INFORMATION
Accepted for publication March 23, 2001.
From the Abarbanel Mental Health Center, Bat-Yam, Israel (Drs Shamir,
Barak, Shalman, and Elizur); Sackler Faculty of Medicine (Drs Shamir, Barak,
Shalman, Elizur, and Weizman), Department of Neurobiochemistry, Faculty of
Life Sciences (Dr Zisapel), and Department of Psychology (Mr Tarrasch), Tel
Aviv University, Neurim Pharmaceuticals Ltd (Drs Laudon and Zisapel), and
Tel Aviv Mental Health Center (Dr Weizman), Tel Aviv, Israel.
Corresponding author and reprints: Eyal Shamir, MD, Abarbanel Mental
Health Center, 15 KKL St, Bat-Yam 59100, Israel (e-mail: drshamir{at}hotmail.com).
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